5-HT1D receptors inhibit the monosynaptic stretch reflex by modulating C-fiber activity

Ana M. Lucas-Osma, Yaqing Li, Katie Murray, Shihao Lin, Sophie Black, Marilee J. Stephens, Andrew H. Ahn, Cj Heckman, Keith K. Fenrich, Karim Fouad, David J. Bennett*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The monosynaptic stretch reflex (MSR) plays an important role in feedback control of movement and posture but can also lead to unstable oscillations associated with tremor and clonus, especially when increased with spinal cord injury (SCI). To control the MSR and clonus after SCI, we examined how serotonin regulates the MSR in the sacrocaudal spinal cord of rats with and without a chronic spinal transection. In chronic spinal rats, numerous 5-HT receptor agonists, including zolmitriptan, methylergonovine, and 5-HT, inhibited the MSR with a potency highly correlated to their binding affinity to 5-HT1D receptors and not other 5-HT receptors. Selective 5-HT1D receptor antagonists blocked this agonist-induced inhibition, although antagonists alone had no action, indicating a lack of endogenous or constitutive receptor activity. In normal uninjured rats, the MSR was likewise inhibited by 5-HT, but at much higher doses, indicating a supersensitivity after SCI. This supersensitivity resulted from the loss of the serotonin transporter SERT with spinal transection, because normal and injured rats were equally sensitive to 5-HT after SERT was blocked or to agonists not transported by SERT (zolmitriptan). Immunolabeling revealed that the 5-HT1D receptor was confined to superficial lamina of the dorsal horn, colocalized with CGRP-positive C-fibers, and eliminated by dorsal rhizotomy. 5-HT1D receptor labeling was not found on large proprioceptive afferents or α-motoneurons of the MSR. Thus serotonergic inhibition of the MSR acts indirectly by modulating C-fiber activity, opening up new possibilities for modulating reflex function and clonus via pain-related pathways. NEW & NOTEWORTHY Brain stem-derived serotonin potently inhibits afferent transmission in the monosynaptic stretch reflex. We show that serotonin produces this inhibition exclusively via 5-HT1D receptors, and yet these receptors are paradoxically mostly confined to C-fibers. This suggests that serotonin acts by gating of C-fiber activity, which in turn modulates afferent transmission to motoneurons. We also show that the classic supersensitivity to 5-HT after spinal cord injury results from a loss of SERT, and not 5-HT1D receptor plasticity.

Original languageEnglish (US)
Pages (from-to)1591-1608
Number of pages18
JournalJournal of neurophysiology
Volume121
Issue number5
DOIs
StatePublished - May 1 2019

Keywords

  • Motoneuron
  • Nociceptive
  • Pain
  • Serotonin
  • Spasticity
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience(all)
  • Physiology

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    Lucas-Osma, A. M., Li, Y., Murray, K., Lin, S., Black, S., Stephens, M. J., Ahn, A. H., Heckman, C., Fenrich, K. K., Fouad, K., & Bennett, D. J. (2019). 5-HT1D receptors inhibit the monosynaptic stretch reflex by modulating C-fiber activity. Journal of neurophysiology, 121(5), 1591-1608. https://doi.org/10.1152/jn.00805.2018